That finding was reported Monday by two Princeton economists, Angus Deaton, who last month won the 2015 Nobel Memorial Prize in Economic Science, and Anne Case. Analyzing health and mortality data from the Centers for Disease Control and Prevention and from other sources, they concluded that rising annual death rates among this group are being driven not by the big killers like heart disease and diabetes but by an epidemic of suicides and afflictions stemming from substance abuse: alcoholic liver disease and overdoses of heroin and prescription opioids.

The analysis by Dr. Deaton and Dr. Case may offer the most rigorous evidence to date of both the causes and implications of a development that has been puzzling demographers in recent years: the declining health and fortunes of poorly educated American whites. In middle age, they are dying at such a high rate that they are increasing the death rate for the entire group of middle-aged white Americans, Dr. Deaton and Dr. Case found.

The mortality rate for whites 45 to 54 years old with no more than a high school education increased by 134 deaths per 100,000 people from 1999 to 2014.

“It is difficult to find modern settings with survival losses of this magnitude,” wrote two Dartmouth economists, Ellen Meara and Jonathan S. Skinner, in a commentary to the Deaton-Case analysis that was published in Proceedings of the National Academy of Sciences.

“Wow,” said Samuel Preston, a professor of sociology at the University of Pennsylvania and an expert on mortality trends and the health of populations, who was not involved in the research. “This is a vivid indication that something is awry in these American households.”

Dr. Deaton had but one parallel. “Only H.I.V./AIDS in contemporary times has done anything like this,” he said.

In contrast, the death rate for middle-aged blacks and Hispanics continued to decline during the same period, as did death rates for younger and older people of all races and ethnic groups.

Middle-aged blacks still have a higher mortality rate than whites — 581 per 100,000, compared with 415 for whites — but the gap is closing, and the rate for middle-aged Hispanics is far lower than for middle-aged whites at 262 per 100,000.

David M. Cutler, a Harvard health care economist, said that although it was known that people were dying from causes like opioid addiction, the thought was that those deaths were just blips in the health care statistics and that over all everyone’s health was improving. The new paper, he said, “shows those blips are more like incoming missiles.”

Dying in Middle Age

Dr. Deaton and Dr. Case (who are husband and wife) say they stumbled on their finding by accident, looking at a variety of national data sets on mortality rates and federal surveys that asked people about their levels of pain, disability and general ill health.

Dr. Deaton was looking at statistics on suicide and happiness, skeptical about whether states with a high happiness level have a low suicide rate. (They do not, he discovered; in fact, the opposite is true.) Dr. Case was interested in poor health, including chronic pain because she has suffered for 12 years from disabling and untreatable lower back pain.

Dr. Deaton noticed in national data sets that middle-aged whites were committing suicide at an unprecedented rate and that the all-cause mortality in this group was rising. But suicides alone, he and Dr. Case realized, were not enough to push up overall death rates, so they began looking at other causes of death. That led them to the discovery that deaths from drug and alcohol poisoning also increased in this group.